Certain pyrrolopyridine derivatives: novel CRF1 specific ligands

ABSTRACT

Disclosed are compounds of the formula:  
                 
 
     wherein  
     Ar is optionally substituted aryl or heteroaryl  
     R 1  is hydrogen or alkyl;  
     R 7  is hydrogen or alkyl;  
     R 2  is hydrogen, halogen, alkyl or alkoxy; or  
     R 1  and R2 taken together with the ring to which they are attached form a 5-9 membered saturated or aromatic ring optionally having a hetero atom selected from oxygen, sulfur or nitrogen;  
     R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl groups; or  
     R 3  and R 4  together with the nitrogen atom to which they are attached form a 5-8 membered ring; and  
     R 5  is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy or thioalkoxy having 1-6 carbon atoms,  
     which compounds are highly selective partial agonists or antagonists at human Corticotropin-Releasing Factor 1 (CRF1) receptors and are useful in the diagnosis and treatment of treating stress related disorders such as post trumatic stress disorder (PTSD) as well as depression, headache and anxiety.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to novel substituted pyrrolopyridinederivatives which selectively bind to Corticotropin-Releasing Factor(CRF) receptors. More specifically, it relates totetrahydro-5H-pyrido[2,3-b]indol-4-amines,9H-pyrido[2,3-b]indol-4-amines, and 1H-pyrrolo[2,3-b]pyridin-4-amines,and their use as antagonists of Corticotropin-Releasing Factor in thetreatment of various disease states.

[0003] 2. Description of the Related Art

[0004] Corticotropin-releasing factor (CRF) antagonists are mentioned inU.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides andpyrazoline derivatives, respectively. The importance of CRF antagonistsis described in the literature, for example, as discussed in U.S. Pat.No. 5,063,245, which is incorporated herein by reference in itsentirety. CRF antagonists are considered effective in the treatment of awide range of diseases including stress-related illnesses, such asstress-induced depression, anxiety, and headache. Other diseasesconsidered treatable with CRF antagonists are discussed in U.S. Pat. No.5,063,245 and Pharmin. Rev., 43: 425-473 (1991).

[0005] International application WO 9413676 A1 disclosespyrrolo[2,3-d]pyrimidines as having Corticotropin-Releasing Factorantagonist activity. J. Het. Chem. 9, 1077 (1972) describes thesynthesis of 9-Phenyl-pyrrolo[3,2-d]pyrimidines.

SUMMARY OF THE INVENTION

[0006] This invention provides novel compounds of Formula I whichinteract with CRF receptors. Further, the invention providespharmaceutical compositions comprising compounds of Formula I. Itfurther relates to the use of such compounds and compositions intreating treating stress related disorders such as post traumatic stressdisorder (PTSD) as well as depression, headache and anxiety.Accordingly, a broad embodiment of the invention is directed to acompound of Formula I:

[0007] wherein

[0008] Ar is optionally substituted aryl or heteroaryl;

[0009] R₁ is hydrogen or alkyl;

[0010] R₇ is hydrogen or alkyl;

[0011] R₂ is hydrogen, halogen, alkyl or alkoxy; or

[0012] R₁ and R₂ taken together with the ring to which they are attachedform a 5-9 membered saturated or aromatic ring optionally having ahetero atom selected from oxygen, sulfur or nitrogen;

[0013] R₃ and R₄ are independently hydrogen, alkyl, cycloalkyl, aryl orheteroaryl groups; or

[0014] R₃ and R₄ together with the nitrogen atom to which they areattached form a 5-8 membered ring; and

[0015] R₅ is hydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms, or straight or branched chain lower alkoxy orthioalkoxy having 1-6 carbon atoms.

[0016] The compounds of the invention are highly selective partialagonists or antagonists at CRF receptors and are useful in the diagnosisand treatment of stress related disorders such as post trumatic stressdisorder (PTSD) as well as depression and anxiety.

[0017] Thus, the invention provides compounds, includingpharmaceutically acceptable salts of the compounds of formula I, andpharmaceutical compositions for use in treating disease statesassociated with Corticotropin-Releasing Factor. The invention furtherprovides methods including animal models relevant to the evaluation ofthe interaction of the compounds of the invention with CRF receptors.This interaction results in the pharmacological activities of thesecompounds.

DETAILED DESCRIPTION OF THE INVENTION

[0018] In addition to the novel compounds of the instant inventiondescribed by general formula I above, the invention encompassescompounds of formula IA:

[0019] wherein

[0020] Ar is phenyl, 2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4- or5-pyrimidinyl, each of which is monosubstituted or optionally di- ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy,provided that at least one of the ortho positions of Ar is substituted;

[0021] R₁ is hydrogen or lower alkyl;

[0022] R₇ is hydrogen or alkyl;

[0023] R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy; or

[0024] R₁ and R₂ taken together represent —(CH₂)_(n)—A—(CH₂)_(m)— wheren is 2, 3 or 4, A is methylene, oxygen, sulfur or NR_(6,) wherein R₆ ishydrogen or lower alkyl, and m is 0, 1 or 2; or

[0025] R₁ and R₂ taken together represent —CH═E—CH═CH—, where E is CH orN;

[0026] R₃ and R₄ are not both hydrogen and independently represent

[0027] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0028] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0029] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0030] R₃ and R₄ taken together represent —(CH₂)n—G—(CH₂)_(m)—

[0031] where n is 2,or 3;

[0032] m is 1, 2 or 3; and

[0033] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0034] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0035] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0036] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0037] Preferred compounds of formula I are those where Ar is adisubstituted aryl or heteroaryl group having substituents in one orthoposition and the para position. More preferred compounds of formula Iare those where Ar is a trisubstituted aryl or heteroaryl group havingsubstituents in both ortho positions and the para position, i.e., a 2,4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl.The preferred aryl substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0038] Other preferred compounds of formula I are those where the NR₃R₄group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino.

[0039] In compounds of formula I, R₅ is preferably lower alkyl and, morepreferably, methyl; and R₇ is preferably hydrogen.

[0040] In still other preferred compounds of formula I, R₁ and R₂ takentogether represent —(CH₂)_(n)—A—(CH₂)_(m)— where n is 2, 3 or 4, A ismethylene, oxygen, sulfur or NMe, and m is 0, 1 or 2.

[0041] The invention further provides compounds of formula II

[0042] wherein

[0043] Ar is phenyl, 2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4- or5-pyrimidinyl, each of which is monosubstituted or optionally di- ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy,provided that at least one of the ortho positions of Ar is substituted;

[0044] R₇ is hydrogen or alkyl;

[0045] R₃ and R₄ are not both hydrogen and independently represent

[0046] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0047] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0048] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0049] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0050] where n is 2,or 3;

[0051] m is 1, 2 or 3; and

[0052] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0053] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0054] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0055] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0056] Preferred compounds of formula II are those where Ar is adisubstituted aryl or heteroaryl group having substituents in one orthoposition and the para position. More preferred compounds of formula IIare those where Ar is a trisubstituted aryl or heteroaryl group havingsubstituents in both ortho positions and the para position, i.e., a 2,4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl.The preferred aryl substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0057] Other preferred compounds of formula II are those where the NR₃R₄group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino.

[0058] In yet other preferred compounds of formula II, R₇ is hydrogen.

[0059] The invention further provides compounds of formula III

[0060] wherein

[0061] R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy;

[0062] R₇ is hydrogen or alkyl;

[0063] R₃ and R₄ are independently represent

[0064] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0065] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0066] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0067] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0068] where n is 2, or 3;

[0069] m is 1,2or 3; and

[0070] G is methylene, 1,2 phenylene, oxygen, sulfur or NR_(6,)

[0071] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0072] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0073] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0074] Preferred compounds of formula III are those where at least oneof R_(a), R_(b), or R_(c) is present in one of the two ortho positionsof the phenyl group to which they are attached. More preferred compoundsof formula III are those where at least two of R_(a), R_(b), or R_(c)are present in one ortho position and the para position. Still morepreferred compounds of formula III are those where the R_(a), R_(b), orR_(c) substituents are present in both ortho positions and the paraposition, i.e., a 2, 4, 6-trisubstituted phenyl group. The preferredR_(a), R_(b), or R_(c) substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0075] Other preferred compounds of formula III are those where theNR₃R₄ group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino.

[0076] In still other preferred compounds of formula III, R₇ ishydrogen.

[0077] The invention further provides compounds of formula IV

[0078] wherein

[0079] E represents CH₂ or NR_(6,) wherein R₆ is hydrogen or loweralkyl;

[0080] R₇ is hydrogen or alkyl;

[0081] R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy;

[0082] R₃ and R₄ are independently represent

[0083] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0084] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0085] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0086] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0087] where n is 2, or 3;

[0088] m is 1, 2 or 3; and

[0089] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0090] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0091] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0092] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0093] Preferred compounds of formula IV are those where at least one ofR_(a), R_(b), or R_(c) is present in one of the two ortho positions ofthe phenyl group to which they are attached. More preferred compounds offormula IV are those where at least two of R_(a), R_(b), or R_(c) arepresent in one ortho position and the para position. Still morepreferred compounds of formula IV are those where the R_(a), R_(b), orR_(c) substituents are present in both ortho positions and the paraposition, i.e., a 2, 4, 6-trisubstituted phenyl group. The preferredR_(a), R_(b), or R_(c) substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0094] Other preferred compounds of formula IV are those where the NR₃R₄group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino. In preferredcompounds of formula IV, E represents carbon.

[0095] In other preferred compounds of formula IV, R₇ is hydrogen.

[0096] The invention further provides compounds of formula V

[0097] wherein

[0098] E represents CH₂ or NR_(6,) wherein R₆ is hydrogen or loweralkyl;

[0099] R₇ is hydrogen or alkyl;

[0100] Ar is phenyl, 2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4- or5-pyrirnidinyl, each of which is monosubstituted or optionally di- ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy,provided that at least one of the ortho positions of Ar is substituted;

[0101] R₃ and R₄ are not both hydrogen and independently represent

[0102] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0103] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0104] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0105] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0106] where n is 2, or 3;

[0107] m is 1,2 or 3; and

[0108] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0109] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0110] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0111] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0112] Preferred compounds of formula V are those where Ar is adisubstituted aryl or heteroaryl group having substituents in one orthoposition and the para position. More preferred compounds of formula Vare those where Ar is a trisubstituted aryl or heteroaryl group havingsubstituents in both ortho positions and the para position, i.e., a 2,4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl.The preferred aryl substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0113] Other preferred compounds of formula V are those where the NR₃R₄group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino. In preferredcompounds of formula V, E represents carbon.

[0114] Yet other preferred compounds of formula V are those where R₇ ishydrogen.

[0115] The invention further provides compounds of formula VI

[0116] wherein

[0117] E represents CH₂ or NR₆, wherein R₆ is hydrogen or lower alkyl;

[0118] R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy;

[0119] R₇ is hydrogen or alkyl;

[0120] R₃ and R₄ are independently represent

[0121] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0122] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0123] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0124] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0125] where n is 2, or 3;

[0126] m is 1, 2 or 3; and

[0127] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0128] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0129] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0130] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0131] Preferred compounds of formula VI are those where at least one ofR_(a), R_(b), or R_(c) is present in one of the two ortho positions ofthe phenyl group to which they are attached. More preferred compounds offormula VI are those where at least two of R_(a), R_(b), or R_(c) arepresent in one ortho position and the para position. Still morepreferred compounds of formula VI are those where the R_(a), R_(b), orR_(c) substituents are present in both ortho positions and the paraposition, i.e., a 2, 4, 6-trisubstituted phenyl group. The preferredR_(a), R_(b), or R_(c) substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0132] Other preferred compounds of formula VI are those where the NR₃R₄group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino. In preferredcompounds of formula VI, E represents carbon.

[0133] In yet other referred compounds of formula VI, R₇ is hydrogen.

[0134] The invention further provides compounds of formula VII

[0135] wherein

[0136] E represents CH₂ or NR₆, wherein R₆ is hydrogen or lower alkyl;

[0137] Ar is phenyl, 2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4- or5-pyrimidinyl, each of which is monosubstituted or optionally di- ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy,provided that at least one of the ortho positions of Ar is substituted;

[0138] R₇ is hydrogen or alkyl;

[0139] R₃ and R₄ are not both hydrogen and independently represent

[0140] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0141] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0142] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0143] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0144] where n is 2, or 3;

[0145] m is 1,2or 3; and

[0146] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0147] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrimidinyl, or

[0148] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and

[0149] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0150] Preferred compounds of formula VII are those where Ar is adisubstituted aryl or heteroaryl group having substituents in one orthoposition and the para position. More preferred compounds of formula VIIare those where Ar is a trisubstituted aryl or heteroaryl group havingsubstituents in both ortho positions and the para position, i.e., a 2,4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl.The preferred aryl substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0151] Other preferred compounds of formula VII are those where theNR₃R₄ group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino. In preferredcompounds of formula VII, E represents carbon.

[0152] In still other compounds of formula VII, R₇ is hydrogen.

[0153] The invention also provides compounds of formula VIII:

[0154] wherein

[0155] R₁ is hydrogen or lower alkyl;

[0156] R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy;

[0157] Ar is phenyl, 2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4- or5-pyrirnidinyl, each of which is monosubstituted or optionally di- ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy,provided that at least one of the ortho positions of Ar is substituted;

[0158] R₇ is hydrogen or alkyl;

[0159] R₃ and R₄ are not both hydrogen and independently represent

[0160] hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono-or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;

[0161] phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;

[0162] cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or

[0163] R₃ and R₄ taken together represent —(CH₂)_(n)—G—(CH₂)_(m)—

[0164] where n is 2, or 3;

[0165] m is 1,2 or 3; and

[0166] G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆,

[0167] wherein R₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or3-thienyl, or 2-, 4-, or 5-pyrinmidinyl, or

[0168] R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-5 pyrimidinylalkyl, where each alkyl islower alkyl; and

[0169] R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.

[0170] Preferred compounds of formula VIII are those where Ar is adisubstituted aryl or heteroaryl group having substituents in one orthoposition and the para position. More preferred compounds of formula VIIIare those where Ar is a trisubstituted aryl or heteroaryl group havingsubstituents in both ortho positions and the para position, i.e., a 2,4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl.The preferred aryl substituents are lower alkyl groups or halogen,particularly fluorine. More preferred aryl substituents are methylgroups.

[0171] Other preferred compounds of formula VIII are those where theNR₃R₄ group is a disubstituted amino group, e.g., dialkyl amino. Aparticularly preferred NR₃R₄ group is dipropylamino.

[0172] In still other preferred compounds of formula VIII, R₁ and R₂ areindependently alkyl groups. In more preferred compounds of formula VIII,R₁ and R₂ are both methyl.

[0173] In the compounds of the invention, preferred NR₃R₄ groups includethe following:

[0174] Representative compounds of the present invention, which areencompassed by Formula I, include, but are not limited to the compoundsin FIG. I and their pharmaceutically acceptable salts. Non-toxicpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic phamaceuticallyacceptable addition salts.

[0175] The present invention also encompasses the acylated prodrugs ofthe compounds of Formula I. Those skilled in the art will recognizevarious synthetic methodologies which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds encompassed by Formula I.

[0176] By aryl or “Ar” is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyi, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

[0177] By aryl or “Ar” is also meant heteroaryl groups where heteroarylis defined as 5, 6, or 7 membered aromatic ring systems having at leastone hetero atom selected from the group consisting of nitrogen, oxygenand sulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl,pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl,quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionallybe substituted with, e.g., halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, andhydroxy.

[0178] By alkyl and lower alkyl is meant straight and branched chainalkyl groups having from 1-6 carbon atoms. Specific non-limitingexamples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl.

[0179] By lower alkoxy and alkoxy is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms.

[0180] By thioalkoxy or alkylthio is meant a group of the formula-S-alkyl, where the alkyl is straight or branched chain alkyl havingfrom 1-6 carbon atoms.

[0181] By halogen is meant fluorine, chlorine, bromine and iodine.

[0182] The pharmaceutical utility of compounds of this invention areindicated by the following assay for CRF receptor activity.

[0183] Assay for CRF receptor binding activity

[0184] CRF receptor binding was performed using a modified version ofthe assay described by Grigoriadis and De Souza (Biochemical,Pharmacological, and Autoradiographic Methods to StudyCorticotropin-Releasing Factor Receptors. Methods in Neurosciences, Vol.5, 1991). Membrane pellets containing CRF receptors were resuspended in50 mM Tris buffer pH 7.7 containing 10 mM MgCl₂ and 2 mM EGTA andcentrifuged for 10 minutes at 48000 g. Membranes were washed again andbrought to a final concentration of 1500 ug/ml in binding buffer (Trisbuffer above with 0.1% BSA, n 0.15 M bacitracin and 0.01 mg/mlaprotinin.). For the binding assay, 100 ul of the membrane preparationwas added to 96 well microtube plates containing 100 ul of 125I-CRF (SA2200 Ci/mmol , final concentration of 100 pM) and 50 ul of drug. Bindingwas carried out at room temperature for 2 hours. Plates were thenharvested on a Brandel 96 well cell harvester and filters were countedfor gamma emissions on a Wallac 1205 Betaplate liquid scintillationcounter. Non specific binding was defined by 1 uM cold CRF. IC₅₀ valueswere calculated with the non-linear curve fitting program RS/1 (BBNSoftware Products Corp., Cambridge, Mass.). The IC₅₀ for Compound 1 ofthis invention is 0.011 μM.

[0185] The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0186] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

[0187] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0188] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0189] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0190] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0191] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

[0192] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0193] The compounds of general formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0194] Compounds of general formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0195] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient

[0196] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0197] A representative illustration of methods suitable for thepreparation of compounds of the present invention is shown in Schemes Iand II. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present invention.

[0198] wherein Ar, R₁, R₂, R₃, R₄, and R₅ are as defined above forformula I.

[0199] In the case where a desired compound of the invention that may beprepared according to Scheme I includes R₇ as alkyl, the intermediate2-amino-1-aryl-3-cyanopyrrole is reacted with base and a compound of theformula R₅COCH₂R₇, where R7 is alkyl.

[0200] where A is NH or CH₂, and Ar, R₃, R₄, and R₅ are as defined abovefor formula I..

[0201] As mentioned above, where a desired compound of the inventionthat may be prepared according to Scheme II includes R₇ as alkyl, theintermediate 2-amino-1-aryl-3-cyanopyrrole is reacted with base and acompound of the formula R₅COCH₂R₇, where R₇ is alkyl.

[0202] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0203] One skilled in the art will recognize that modifications may bemade in the present invention without deviating from the spirit or scopeof the invention. The invention is illustrated further by the followingexamples which are not to be construed as limiting the invention orscope of the specific procedures or compositions described herein.

[0204] A mixture of 2,4,6-trimethylaniline (10.5 g 78 mmol),2-hydroxycyclohexanone dimer (8.9 g, 39 mmol) and pTsOH (44 mg) isrefluxed in 100 mL of toluene. Water is removed using a Dean-Starkapparatus. After 2 hours the solution is cooled and malononitrile (5.2g) dissolved in 20 mL toluene is added. The mixture is refluxed foranother 8 hours after which the solvent is removed under reducedpressure. The crude product is triturated with ether and some ethanol,and collected by filtration as a tan solid to afford aminonitrile 1 a.

[0205] Aminonitrile 1 a (1.1 g, 4.0 mmol) prepared above is stirred withanhydrous acetone (1.5 mL), pTsOH (10 mg) and 4A molecular sieves (1 g)in 10 mL benzene at 60° C. for 10 hours. The mixture is then filteredthrough celite pretreated with triethylamine. The volatile solvents areremoved under reduced pressure. The residual material is dissolved in 20mL THF and treated with lithium diisopropylamide (2.0 M, 4 mL) under icecooling. After 1 hour the mixture is poured into water and extractedwith ethyl acetate. The organic layer is subsequently extracted with 5%hydrochloric acid. The aqueous layer is made alkaline with 10N sodiumhydroxide and extracted with dichloromethane. The extract is washed withwater, dried over sodium sulfate, and concentrated to afford2-Methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine1 b as a white solid.

[0206]2-Methyl-6,7,8,9-tetrahydo-9-(2,4,6-trimethylpheny)-5H-pyrido[2,3-b]indol-4-amine(1 b) (470 mg) dissolved in 10 mL dichloroethane is refluxed for 3 hourswith propionyl chloride (0.5 mL). The residual reagents are evaporatedunder reduced pressure. The crude product is partitioned between aqueoussodium carbonate solution and dichloromethane. The organic extract isdried over sodium sulfate and concentrated. The solid, diacylatedproduct is triturated with hexanes and collected by filtration to affordN,N-Dipropionyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-methylphenyl)-5H-pyrido[2,3-b]indol-4-amine 1 c as a white solid.

[0207]N,N-Dipropionyl-2-methyl-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine 1 c (312 mg) is refluxed in 8 mL THF withborane-methylsulfide complex (10 M, 1.2 mL) for 10 hours. After coolingthe solution, it is carefully quenched with 5 mL of methanol. Theresulting solution is refluxed for another 2 hours and thenconcentrated. The dialkylamine product is purified on silica gel using20% ethyl acetate in hexanes as eluant to affordN,N-Dipropyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine(Compound 1) as a white solid, m.p.: 117-118° C.

Example II

[0208] The following compounds are prepared essentially according to theprocedures described in Examples IA-D:

[0209] a)N-Propyl-N-cyclopropylmethyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine(Compound 2).

[0210] b)N-Propyl-N-cyclopropylmethyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indol-4-amine(Compound 3):

[0211] c)N-Butyl-N-Ethyl-2-methyl-6,7,8,9-tetraydro-9-(2,4,6-trimethylpheny)-5H-pyrido[2,3-b]indol-4-amine(Compound 4).

[0212] d)N,N-Butyl-N-Ethyl-2-methyl-9(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indo-4-amine(Compound5).

[0213] e)N-Butyl-N-Ethyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indol-4-amine(Compound 6).

[0214] f) N,N-Dipropyl-1-(2,4,6-trimethylphenyl)-2,5,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-amine(Compound 7).

[0215] g) N-Cyclopropylmethyl-N-propyl-1-(2,4,6-trimethylphenyl)-2,5,6-trimethyl- 1H-pyrrolo[2,3-b]pyridin-4-amine (Compound 8).

[0216] h)N-Butyl-N-ethyl-1-(2,4,6-trimethylphenyl)-2,5,6-trimethyl-1H-pyrrolo[2,3-5b]pyridin-4-amine (Compound 9).

[0217] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or the pharmaceutically acceptable salts thereof wherein Ar is phenyl,2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each ofwhich is monosubstituted or optionally di- or trisubstituted withhalogen, hydroxy, lower alkyl, or lower alkoxy, provided that at leastone of the ortho positions of Ar is substituted; R₁ is hydrogen or loweralkyl; R₇ is hydrogen or alkyl; R₂ is hydrogen, halogen, lower alkyl,lower alkoxy, or thioalkoxy; or R₁ and R₂ taken together represent—(CH₂)_(n)—A—(CH₂)_(m)— wherein is 2, 3 or 4, A is methylene, oxygen,sulfur or NR₆, wherein R₆ is hydrogen or lower alkyl, and m is 0, 1 or2; or R₁ and R₂ taken together represent —CH═E—CH═CH—, where E is CH orN; R₃ and R₄ are not both hydrogen and independently represent hydrogen,lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl or 2-, 4-, or5-pyrimidinyl, each of which is optionally mono- or disubstituted withhalogen, hydroxy, lower alkyl, or lower alkoxy; phenylalkyl, 2-, 3-, or4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrirnidinyl alkyl,where each alkyl is lower alkyl; cycloalkyl having 3-8 carbon atoms,cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of whichis optionally mono or disubstituted with lower alkyl; or R₃ and R₄ takentogether represent —(CH₂)_(n)—G—(CH₂)_(m)— where n is 2, or 3; m is 1, 2or 3; and G is methylene, 1,2 phenylene, oxygen, sulfur or NR₆, whereinR₆ is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-,4-, or 5-pyrimidinyl, or R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl,2- or 3-thienylalkyl, or 2-, 4- or 5-pyrirnidinylalkyl, where each alkylis lower alkyl; and R₅ is hydrogen, halogen, lower alkyl, lower alkoxy,or thioalkoxy.
 2. A compound according to claim 2 wherein R₁ and R₂taken together represent —(CH₂)_(n)—A—(CH₂)_(m)— where n is 2, 3 or 4, Ais methylene, oxygen, sulfur or NMe, and m is 0, 1 or
 2. 3. A compoundaccording to claim 2, wherein Ar is

where R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy.
 4. A compound according to claim 1,wherein Ar is

where R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy.
 5. A compound of the formula:

or the pharmaceutically acceptable salts thereof, wherein E representsCH₂ or NR₆, wherein R₆ is hydrogen or lower alkyl; Ar is phenyl, 2-, 3,-or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which ismonosubstituted or optionally di- or trisubstituted with halogen,hydroxy, lower alkyl, or lower alkoxy, provided that at least one of theortho positions of Ar is substituted; R₃ and R₄ are not both hydrogenand independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or4-pyridyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which isoptionally mono- or disubstituted with halogen, hydroxy, lower alkyl, orlower alkoxy; phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinyl alkyl, where each alkyl islower alkyl; cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or R₃ and R₄ taken together represent—(CH₂)_(n)—G—(CH₂)_(m)— where n is 2, or 3; m is 1, 2 or 3; and G ismethylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ is loweralkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4-, or5-pyrimidinyl, or R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.
 6. A compound according to claim 5, wherein Ar is

where R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy.
 7. A compound according to claim 5,wherein Ar is

where R_(a) represents halogen, hydroxy, lower alkyl, or lower alkoxy;and R_(b) and R_(c) independently represent halogen, hydroxy, loweralkyl, or lower alkoxy.
 8. A compound of the formula:

or the pharmaceutically acceptable salts thereof, wherein E representsCH₂ or NR₆, wherein R₆ is hydrogen or lower alkyl; Ar is phenyl, 2-, 3,-or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which ismonosubstituted or optionally di- or trisubstituted with halogen,hydroxy, lower alkyl, or lower alkoxy, provided that at least one of theortho positions of Ar is substituted; R₃ and R₄ are not both hydrogenand independently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or4-pyridyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which isoptionally mono- or disubstituted with halogen, hydroxy, lower alkyl, orlower alkoxy; phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinyl alkyl, where each alkyl islower alkyl; cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or R₃ and R₄ taken together represent_((CH) ₂)_(n)—G—(CH₂)_(m)— where n is 2, or 3; m is 1,2or 3; and G ismethylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ is loweralkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4-, or5-pyrimidinyl, or R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.
 9. A compound according to claim 8, wherein Ar is

where R_(a), R_(b), and R_(c) independently represent halogen, hydroxy,lower alkyl, or lower alkoxy.
 10. A compound according to claim 8,wherein Ar is

where R_(a) represents halogen, hydroxy, lower alkyl, or lower alkoxy;and R_(b) and R_(c) independently represent halogen, hydroxy, loweralkyl, or lower alkoxy.
 11. A compound according to claim 2 wherein R₁and R₂ taken together represent —CH═A—CH═CH— where A is CH or N.
 12. Acompound according to claim 1 which isN,N-Dipropyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine.13. A compound according to claim 1 which isN-Propyl-N-cyclopropylmethyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4amine.14. A compound according to claim 1 which isN-Propyl-N-cyclopropylmethyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indol-4-amine.15. A compound according to claim 1 which isN-Butyl-N-Ethyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine.16. A compound according to claim 1 which isN,N-Dipropyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indol-4-amine.17. A compound according to claim 1 which isN-Butyl-N-Ethyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indol-4-amine.18. A compound according to claim 1 which isN,N-Dipropyl-l-(2,4,6-trimethylphenyl)-2,5,6-trimethyl-1H-pyrrolo[2,3-b]pyridin4amine.
 19. A compound according to claim 1which isN-Cyclopropylmethyl-N-propyl-1-(2,4,6-trimethylphenyl)-2,5,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-amine.
 20. A compound according to claim 1which is N-Butyl-N-ethyl-1-(2,4,6-trimethylphenyl)-2,5,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4- amine.
 21. A compound of the formula:

or the pharmaceutically acceptable salts thereof wherein R₁ is hydrogenor lower alkyl; R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy; Ar is phenyl, 2-, 3,- or 4-pyridyl, 2- or 3-thienyl, 4 or5-pyrimidinyl, each of which is monosubstituted or optionally di- ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy,provided that at least one of the ortho positions of Ar is substituted;R₇ is hydrogen or alkyl; R₃ and R₄ are not both hydrogen andindependently represent hydrogen, lower alkyl, phenyl, 2-, 3-, or4-pyridyl, 2- or 3-thienyl or 2-, 4, or 5-pyrimidinyl, each of which isoptionally mono- or disubstituted with halogen, hydroxy, lower alkyl, orlower alkoxy; phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrirnidinyl alkyl, where each alkyl islower alkyl; cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl,2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono ordisubstituted with lower alkyl; or R₃ and R₄ taken together represent—(CH₂)_(n)—G—(CH₂)_(m)— where n is 2, or 3; m is 1,2or 3; and G ismethylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ is loweralkyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-, 4-, or5-pyrimidinyl, or R₆ is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or3-thienylalkyl, or 2-, 4- or 5-pyrimidinylalkyl, where each alkyl islower alkyl; and R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, orthioalkoxy.